Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([O:6][CH3:7])[O:4][CH3:5].[F:16][C:17]([F:23])([F:22])[C:18]([O:20]C)=[O:19]>C(OCC)(=O)C>[F:16][C:17]([F:23])([F:22])[C:18]([O-:20])=[O:19].[CH3:1][O:2][Si:3]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[CH3:17])([O:6][CH3:7])[O:4][CH3:5]
Reactant: COC(=O)C(F)(F)F
Reactant: CO[Si](CCc1ccccn1)(OC)OC
Solvent: CCOC(C)=O
Product: CO[Si](CCc1cccc[n+]1C)(OC)OC
Product: O=C([O-])C(F)(F)F

Procedure:
5.0 g of 2-(trimethoxysilylethyl)pyridine and 18 g of ethyl acetate were charged into a 100 mL flask to be dissolved. While stirring the resultant mixed solution with a magnetic stirrer, to the mixed solution, a solution in which 4.2 g of methyl trifluoroacetate was dissolved in 24 g of ethyl acetate was gradually added at room temperature in a nitrogen atmosphere. The reaction mixture was refluxed over 3 days and therefrom, ethyl acetate was distilled of under reduced pressure. The resultant concentrate was dropped into 100 mL of diethyl ether and therefrom, 2-(trimethoxysilylethyl)pyridine and methyl trifluoroacetate as by-products were removed. This purification was repeated three times and then remaining diethyl ether was distilled off under reduced pressure, followed by dissolving the resultant concentrate in methanol to obtain a 30% methanol solution of trimethoxysilylethylmethylpyridinium trifluoroacetate.
Reaction SMILES: O=P(Cl)(Cl)Cl.[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].CN([CH:21]=[O:22])C>>[CH:21]([C:10]1[S:6][C:7]([CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:9]=1)=[O:22]
Reactant: COC(=O)CCCc1cccs1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCCc1ccc(C=O)s1
Temperature: 110 °C
Yield: 83 %

Procedure:
Freshly distilled POCl3 (0.4 MI, 4.12 mmol) was added to a solution of methyl 4-(thiophen-2-yl)butanoate (1.1 g, 5.97 mmol) in dry DMF (0.7 MI) at 0° C. The reaction mixture was further heated to 110° C. for 1.5 h, then cooled to room temperature and quenched with ice water. The Ph of the reaction mixture was adjusted to ˜7 using aqueous Na2CO3 solution. The organic product was extracted with diethyl ether and the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get methyl 4-(5-formylthiophen-2-yl)butanoate (1.0 g, yield 83%), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 9.82 (s, 1H), 7.63-7.61 (d, J=3.7 Hz, 1H), 6.94-6.92 (m, 1H), 3.68 (s, 3H), 2.96-2.91 (t, J=7.5 Hz, 2H), 2.42-2.37 (m, 2H), 2.09-1.99 (m, 2H). MS (ESI) m/z: Calculated for C10H12O3S: 212.05. found: 212.9 (M+H)+
Reaction SMILES: [CH:1]1([O:6][N:7]=[C:8]([C:24]2[N:25]=[C:26]([NH:29]C=O)[S:27][CH:28]=2)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.Cl.CO>O1CCCC1>[CH:1]1([O:6][N:7]=[C:8]([C:24]2[N:25]=[C:26]([NH2:29])[S:27][CH:28]=2)[C:9]([NH:11][CH:12]2[C:22](=[O:23])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=CNc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Nc1nc(C(=NOC2C=CCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A mixture of 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.6 g), conc. hydrochloric acid (1.1 g), methanol (20 ml) and tetrahydrofuran (15 ml) was stirred for 2 hours at room temperature. The reaction mixture was evaporated. The residue was dissolved in an aqueous solution of sodium bicarbonate and the solution was adjusted to pH 3.0 with hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-cyclopenten-1-yl)oxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer)(1.3 g). mp. 201° to 213° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+].CO>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[C:9]([N:23]2[CH:27]=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CC(O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Temperature: -80 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
The reduction was carried out following the procedure described in Example 9. A solution of 180 mg (0.38 mmole) of ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(1H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate in 10 mL of tetrahydrofuran at 0° C. was treated with triethylborane (0.9 mL, lM in tetrahydrofuran). After 2 hrs., the solution was cooled to -80° C. and treated with 30 mg of sodium borohydride followed by 200 μL of methanol. The crude product was purified by silica gel chromatography to yield 111.2 mg (62%) of the title compound.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:17]=[C:16]([C:18](=[O:40])[NH:19][CH2:20][C:21](=[O:39])[N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=4)[CH2:24][CH2:23]3)[NH:15][N:14]=2)[CH:8]=1.C(C1C=C(C=CC=1)C(OC)=O)(=O)C.N1C=CC=N1>C1COCC1.CO.O>[O:39]=[C:21]([N:22]1[CH2:23][CH2:24][CH:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[CH2:26][CH2:27]1)[CH2:20][NH:19][C:18]([C:16]1[CH:17]=[C:13]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:41])=[O:5])[NH:14][N:15]=1)=[O:40]
Reactant: COC(=O)c1cccc(-c2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)[nH]n2)c1
Agent: COC(=O)c1cccc(C(C)=O)c1
Agent: [Li]O
Agent: c1cn[nH]c1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc(-c2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)n[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
LiOH.H2O (32 mg, 0.76 mmol) was added to a stirred mixture of 3-(5-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethylcarbamoyl}-1H-pyrazol-3-yl)-benzoic acid methyl ester (99 mg, 0.2 mmol) (prepared by the method used for the synthesis of Example 102, starting, alternatively from methyl 3-acetylbenzoate to generate the 1H-pyrazole intermediate) in THF:MeOH:H2O (3:2:1, 38 mL) was added, and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure Cold water was then added and the contents were acidified with 10% aqueous HCl, the precipitate was filtered. The solid obtained was purified by recrystallisation form methanol to afford 50 mg (38.1% Yield) of 3-(5-{2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethylcarbamoyl}-2H-pyrazol-3-yl)-benzoic acid. LC/MS [M+H]+: 517, 95.29%. 1H NMR (300 MHz, DMSO-d6): δ13.8 (s, 1H), 13.2 (s, 1H), 8.38 (s, 1H), 8.04 (d, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 7.26 (t, 3H), 7.18 (bs, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:21])[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:29][CH3:30].O.[CH3:32][C:33](C)=O>>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:21])[C:13](=[O:20])[C:14]([CH2:29][CH3:30])([CH2:32][CH3:33])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)CC(=O)C(C)NC(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(CC)(CC)C(=O)C(C)NC(=O)OCc1ccccc1
Yield: 53 %

Procedure:
To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-3-oxopentanoate (3.0 g) in acetone (50 mL) were added potassium carbonate (2.83 g) and iodoethane (2.45 mL), and the mixture was refluxed overnight. After allowing to room temperature, potassium carbonate (2.83 g) and iodoethane(2.45 mL) were added, and the mixture was refluxed for 1 day. After allowing to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=20:1→3:2) to give ethyl 4-{[(benzyloxy) carbonyl]amino}-2,2-diethyl-3-oxopentanoate as a colorless oil (yield: 1.91 g, 53%). To a solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-diethyl-3-oxopentanoate (1.91 g) in methanol (15 mL) was added 10% palladium carbon (containing 50% water, 1.0 g), and the mixture was stirred under a hydrogen atmosphere overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (yield: 920 mg, 99%).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Li].CN(C)[CH:30]=[O:31].C(O)(=O)C>O1CCCC1>[C:1]([Si:5]([CH3:7])([CH3:6])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH:30]=[O:31])=[C:14]([F:19])[C:15]([Cl:18])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)c(F)c1C=O
Yield: 40.9 %

Procedure:
In a manner similar to the method described in example 52a, tert-butyl-[2-(4-chloro-3-fluoro-phenoxy)-ethoxy]-dimethyl-silane (14.3 g, 47 mmol) prepared in example 132a was reacted with lithium diisopropylamine (34 mL, 1.8 M in THF, 61 mmol), N,N-dimethyl-formamide (4.7 mL, 61 mmol) and quenched with acetic acid (14 g, 234 mmol) in tetrahydrofuran to give 6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-chloro-2-fluoro-benzaldehyde as a white solid (Yield: 6.4 g, 41%).
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:19]=[CH:18][CH2:17][C:16]2[C:9]=1[CH:10]=[C:11]1[C:15]=2[C:14]([CH3:20])=[N:13][N:12]1[CH2:21][C@@H:22](O)[CH3:23].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([CH:22]([CH3:23])[CH2:21][N:12]1[C:11]2=[CH:10][C:9]3[C:16]([CH2:17][CH:18]=[CH:19][C:8]=3[O:7][CH3:6])=[C:15]2[C:14]([CH3:20])=[N:13]1)=[N+:33]=[N-:34]
Reactant: COC1=C2C=c3c(c(C)nn3C[C@H](C)O)=C2CC=C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC1=C2C=c3c(c(C)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 82.9 %

Procedure:
0.7 ml (8.52 mmol) of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.1 g (4.26 mmol) of (S)-1-(7-methoxy-3-methyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 2.4 ml (17 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 130 ml of dichloromethane, washed twice with 60 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 60 ml of anhydrous dimethylformamide, treated with 0.55 g (8.46 mmol) of sodium azide and the reaction mixture was heated to 80° for 15 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 80 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1 g (83%) of (RS)-1-(2-azido-propyl)-7-methoxy-3-methyl-1,4-dihydro-indeno[2,1-c]pyrazole was obtained as a dark brown oil.
Reaction SMILES: [C:1]1([N:7]([CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)C=CC=CC=1.N[CH2:29]CCNC1C(C)=CC=CN=1.CI.O>CS(C)=O>[NH2:17][CH2:16][CH2:15][CH2:14][N:7]([C:8]1[C:13]([CH3:29])=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:1]
Reactant: Cc1cccnc1NCCCN
Reactant: O=C1c2ccccc2C(=O)N1CCCN(c1ccccc1)c1ccccn1
Solvent: CI
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccnc1N(C)CCCN
Reaction time: 1 h
Yield: 801.1 %

Procedure:
A mixture of 3-methyl-2-bromopyridine (15 g), 1,3-diaminopropane (37.3 g) and pyridine (10 ml) was heated under reflux for 3 hr. After stripping, the residue was treated with 2N sodium hydroxide and the product extracted into chloroform. The extract was dried, stripped and the residue distilled at reduced pressure to give 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) bp 100° C., 0.09 mm Hg. (ii) Sodium hydride (1.11 g) was dissolved in DMSO (20 ml) at 70°-75° C. The solution was cooled and 2-(3-aminopropylamino)-3-methylpyridine (6.94 g) in DMSO (10 ml) added at room temperature. Methyl iodide (6.56g) in DMSO (20 ml) was added dropwise maintaining the temperature at 20°-25° C. After a further 1 hr, water (100 ml) was added and the mixture extracted with chloroform. The chloroform extract was washed with 2N hydrochloric acid. The pH of the acid extract was raised to 9.5 and extracted with chloroform. The pH was raised further to 14 and again extracted with chloroform. After stripping the final extract, the residue was taken back up in water and the product extracted out again with ether. After drying (K2CO3), stripping the ether extract gave 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (4.46 g) as an oil which was used without further purification. (iii) 2-[N-(3-aminopropyl)-N-methylamino]-3-methylpyridine (1.5 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.46 g) were heated together under reflux in pyridine (10 ml) for 20 hr. The mixture was stripped and the residue triturated with water (pH adjusted to 7 with 6N hydrochloric acid) until a solid (2.1 g) was obtained. This was chromatographed (silica gel, 1-3% methanol/chloroform) and crystallised from acetone/water to give 2-[3-[N-methyl-N-(3-methylpyrid-2-yl)amino]-propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.48 g (22%) mp 83°-85° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][N:6]=2>N1C(C)=CC=CC=1C.OC1CCNCC1>[OH-:12].[OH:12][C:11]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3](=[O:19])[C:2]=1[NH+:4]1[CH2:5][CH2:10][CH:11]([OH:12])[CH2:2][CH2:3]1
Reactant: O=c1c(Br)c(O)c2cccnc2n1-c1ccccc1
Agent: OC1CCNCC1
Solvent: Cc1cccc(C)n1
Product: O=c1c([NH+]2CCC(O)CC2)c(O)c2cccnc2n1-c1ccccc1
Product: [OH-]
Temperature: 100 °C

Procedure:
A solution of 3-bromo-4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one (1 g) in a mixture of 2,6-lutidine (5 mL) and 4-hydroxy-piperidine (3.12 g) was heated at 100° C. for 32 hours. The lutidine was removed by evaporation under high vacuum. The residue was dissolved in CH3CN(20): H2O(80): CH3CO2H(1) and separated by reversed phase preparative HPLC (Whatman Magnum 40 with Partisil 40/ODS-3). The fractions containing the desired product were combined and evaporated to yield a partially crystalline material which was recrystallized from isopropanol to yield the desired product, m.p. 256°-258° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]\[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:67][CH2:68][CH2:69][C:70]([OH:72])=[O:71].C([BH3-])#N.[Na+].Cl>O1CCOCC1.O>[C:70]([CH2:69][CH2:68][CH2:67][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:26]([O:60][CH3:61])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:58][CH3:59])[C@@H:36]([CH3:57])[C:37]([NH:39][C@H:40](/[CH:48]=[CH:49]\[CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:72])=[O:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\Cc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C\Cc1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
14.5 mg (16 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3Z)-1,5-diphenylpent-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 17) was dissolved in 1 mL dioxane/water (1:1) and mixed with 20.4 μL (32 μmol) of a 15% aqueous solution of 4-oxobutanoic acid. The batch was then stirred for one hour at 100° C. After cooling to RT, 1.1 mg (17 μmol) sodium cyanoborohydride was added and the mixture was adjusted to a pH of 3 by adding approx. 150 μL 0.1N hydrochloric acid. The batch was then stirred for two hours more at 100° C. Then 1.1 mg (17 μmol) sodium cyanoborohydride was added again and the mixture was next adjusted to a pH of 3 by adding approx. 300 μL 0.1N hydrochloric acid. The batch was then stirred again for two hours at 100° C. If the reaction was still incomplete, this procedure was repeated once more. Finally, the batch was concentrated and the raw product was purified by preparative HPLC and lyophilized from dioxane, thereby yielding 13.1 mg (93% of the theoretical) of the title compound in the form of a white solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])[CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O.C(CCO)CC/C=C\C/C=C\C/C=C\C/C=C\CCCC(O)=O>>[CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([OH:23])/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCCCC(O)C=CCC=CCC=CCC=CCCCC(=O)O
Agent: CCCC[C@@H](O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Agent: O=C(O)CCC/C=C\C/C=C\C/C=C\C/C=C\CCCCCO
Product: CCCCC(O)/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reaction time: 0.33 h

Procedure:
Neutrophil adhesion: Isolated neutrophils were resuspended in M199 containing 1% BSA with a final concentration of 3×106 cells per ml. Cells suspensions (1 ml) were incubated with or without a test compound, 16(S)-HETE, 16(R)-HETE, or 20-HETE (concentrations 1 nM to 10 μM) for 10 min and then placed into gelatin-coated wells and further incubated for 20 min at 37° C. The wells were washed three times with 0.5 ml of solution M199 to remove non-adherent cells. The adherent cells were then removed by addition of 0.4 ml of 0.25% trypsin-EDTA in 0.1M PBS to the gelatin-coated wells and incubation for 10 min at 37° C. The incubates were transferred and the wells were washed with 0.1 ml of M199 solution. The amount of cells in combined solutions was counted. In some experiments, the adhesion of neutrophils was stimulated by addition of 1 U/ml of thrombin to neutrophil suspension immediately prior to the transfer of cells to the wells. Experiments were performed in duplicates for each concentration of HETE. The inhibition of adhesion was expressed as percent of cells remaining in suspension (non-adherent) relative to control. The range of adherent PMNs in control incubations was 6 to 23%. This was increased two-fold in the presence of thrombin.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](C(F)(F)F)=[CH:6][CH:5]=1)=[O:3].C(C(O)=O)=O.O.Cl>>[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=CC(=O)O
Solvent: O
Product: CC(=O)c1ccccc1

Procedure:
This procedure required close temperature control to avoid tar formation. To avoid this, the method was modified to a two-step process wherein the intermediate alpha-hydroxy acid was isolated and pyrolyzed separately. 4-Trifluoromethylacetophenone (75.2 g, 0.4 mole) and OHCCO2H.H2O (75.2 g) were heated neat at 79°-80° for 8 hr. The hot mixture was poured into diluted aqueous HCl (7.5 ml of concd HCl and 800 ml of H2O) with stirring. The aqueous mixture was extracted with Et2O (2 × 250 ml), and the aqueous phase was discarded. The extract was washed with H2O (2 × 100 ml), and dried (Na2SO4), and Et2O was removed (aspirator). The resulting residue was digested with hot CHCl3 (100 ml) and the mixture was concentrated to a volume of 80-85 ml. Petroleum ether (30°-60°, 250 ml), was added with stirring. The resulting precipitate was collected and washed with petroleum ether (100 ml). (Removal of petroleum ether from the combined washes and filtrate yielded unreacted acetophenone, 39.3 g, 52.3%, suitable for recycling.) The solid was digested again with CHCl3 (150 ml), filtered, and air-dried to yield 2-hydroxy-3-(4-trifluoromethylbenzoyl)propionic acid (31.2 g, 62%), mp 118°-120°. Anal. (C11H9F3O4) C, H. The alpha-hydroxy acid was heated neat under vacuum (1-2 mm) in an oil bath until the internal temperature reached 155°. The temperature was increased to 160° over 40 minutes to complete the elimination of H2O. The flask was allowed to cool and crystallization of the title acrylic acid usually began at around 138°. The product was sufficiently pure for conversion to isonicotinic acid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][C:16]1[CH:20]=[CH:19][N:18]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:36]=[CH:35][C:34](C2C=CC(N3C=CC(CC(O)=O)=C3)=CC=2)=[CH:33][CH:32]=1)#[N:30].C([C@H]1COC(=O)N1)C1C=CC=CC=1.CCOC(C)=O>CCOC(C)=O.CC(OC)(C)C.C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][C:16]1[CH:20]=[CH:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:34]3[CH:35]=[CH:36][C:31]([C:29]#[N:30])=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccn(-c2ccc(F)cc2)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: N#Cc1ccc(-c2ccc(-n3ccc(CC(=O)O)c3)cc2)cc1
Agent: O=C1N[C@@H](Cc2ccccc2)CO1
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2ccc(-n3ccc(CC(=O)N4C(=O)OC[C@@H]4Cc4ccccc4)c3)cc2)cc1
Yield: 59 %

Procedure:
As in Example 14(a) for 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4-fluorophenyl)-1H-pyrrol-3-yl]-ethanone, 2-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-acetic acid and 4(S)-benzyl-2-oxazolidinone were coupled. Flash column chromatography with 10-25% EtOAc/hex to CH2Cl2 stepwise gradient eluant and subsequent trituration with EtOAc/MTBE/hex provided in 59% yield 1-(4(S)-benzyl-oxazolidin-2-on-3-yl)-2-[1-(4′-cyanobiphenyl-4-yl)-1H-pyrrol-3-yl]-ethanone as a pale yellow amorphous solid. 1H NMR: δ 7.75 (d, 2H, J=8.8 Hz), 7.70 (d, 2H, J=8.5 Hz), 7.65 (d, 2H, J=8.8 Hz), 7.49 (d, 2H, J=8.8 Hz), 7.32-7.25 (m, 3H), 7.17-7.15 (m, 3H), 7.12 (t, 1H, J=2.8 Hz), 6.40 (dd, 1H, J=1.7, 2.8 Hz), 4.74-4.68 (m, 1H), 4.31-4.16 (m, 4H), 3.29 (dd, 1H, J=2.9, 13.6 Hz), 2.80 (dd, 1H J=9.4, 13.4 Hz). Anal. Calculated for C29H23N3O3: C, 75.47; H, 5.02; N, 9.11. Found: C, 75.36; H, 5.08; N, 9.15.